Critical to the diagnosis and treatment of certain inflammatory, hematologic and immune disorders is the preparation of reagents that exhibit binding specificity for defined molecular targets in the immune system. It is of paramount importance when using such reagents therapeutically to avoid the adverse non-specific toxic effects that are associated with many current chemotherapeutic or “immunomodulatory” therapeutic agents.
Antibody reagents have been used extensively for the diagnosis and therapy of immune disorders. In the case of immune B cells and B cell derived leukemias, the immunoglobulin (Ig) molecule displayed on the surface of the B cell provides an attractive target for detection by a specific reagent.
For example, antibodies that bind specifically to the binding site of the Ig molecule (i.e., the idiotype) have been developed as potential therapeutic reagents for disease associated B-cell clones. However, practical concerns, including the possible requirement of tailoring therapies for the specific disease-associated clone of each patient, has tempered enthusiasm for this approach despite evidence from experimental systems of the potential efficacy of this type of targeted therapy. Recently, several pharmaceutical companies have received regulatory approval, and successfully brought to market for the treatment of lymphoma, a recombinant antibody specific for the human B-cell surface marker, CD20. However, this reagent is less than optimal as it appears to non-selectively delete all human mature B cells. Furthermore, although antibody reagents can be readily engineered by genetic manipulation to provide useful binding specificities not readily available in nature, there are high costs associated with producing sufficient quantities of reagent in mammalian expression systems for therapeutic intervention.
Thus, a need exists for methods to produce reagents that are engineered to better target immune cells including β-cell cancers which can be expressed economically in microbial expression systems.